The present invention relates to physiology, diagnostics, and neuroscience in general, and, more particularly, to functional magnetic resonance imaging, which is commonly known as xe2x80x9cfMRI.xe2x80x9d
The human brain comprises billions of neurons that interact in a manner that diagnosticians have long sought to fully understand. One fact that is known about the operation of the brain is that the brain responds to a stimulus with a cascade of neuronal events. For the purposes of this specification, a xe2x80x9cstimulusxe2x80x9d is defined as an agent, action, or condition, either internal or external, that elicits, inhibits, accelerates, or decelerates a physiological or psychological activity or response. A stimulus includes,.but is not limited to visual, audible, tactile, olfactory, sapid, electrical, and chemical input. For example, the brain can receive a stimulus through one of the sense organs or not, as in, for example, the case of neuro-pharmacological agents.
FIG. 1 depicts a diagram of a stimulus that triggers a cascade of neuronal events, as is well-known in the prior art. As shown in FIG. 1, each neuronal event is represented by a circle, and each neuronal event is triggered by either: (i) the stimulus, (ii) another neuronal event, or (iii) the confluence of two or more neuronal events. Some neuronal events trigger other neuronal events and some do not. Although the cascade depicted in FIG. I comprises several dozen neuronal events, a typical cascade in the human brain in response to a typical stimulus comprises hundreds or thousands of neuronal events or more.
The topology of a cascade is causal, and, therefore, if the same stimulus is administered to one person under identical circumstances but at different times, the same cascade will occur. Furthermore, because the operation of the brain is considered to be at least partially the result of genetic factorsxe2x80x94in contrast to wholly the result of environmental factorsxe2x80x94it is hypothesized that if the same stimulus is administered to different people under similar circumstances, a similar cascade will be generated in both people. If true, this hypothesis is useful because it suggests that a variation in a person""s observed cascade from the predicted cascade is an indication of a pathological condition in that person.
To determine whether a person""s cascade is nominal or not, a diagnostician must be able to: (1) detect and identify each neuronal event that makes up a cascade, (2) detect the sequence (or relative timing) in which the neuronal events that make up the cascade occur, and (3) distinguish the neuronal events that make up the cascade from other contemporaneous neuronal events that are not part of the cascade.
Two well-known techniques for detecting neuronal events are electroencephalography (commonly known as xe2x80x9cEEGxe2x80x9d) and magnetic encephalography (commonly known as xe2x80x9cMEGxe2x80x9d). Although these techniques are advantageous for detecting the existence and relative timing of temporally-disparate neuronal events, they are not well-suited for distinguishing between contemporaneous neuronal events.
As is well-known in the prior art, contemporaneous neuronal events can be distinguished from each other based on where in the brain they occur. For example, each neuronal event occurs not throughout the entire brain or at different places in the brain at different times but always at a specific spatially-defined region of the brain. In other words, each neuronal event always occurs in the same region of the brain each time it occurs and nowhere else. This fact is useful because it means that contemporaneous neuronal events can be distinguished based on where they occur (ie., on their spatial disparity).
Another well-known technique for studying brain activity is known as functional magnetic resonance imaging. The principal advantage of functional magnetic resonance imaging over electroencephalography and magnetic encephalography is that it is accurate at detecting whether a neuronal event has occurred at a specific region of the brain or not, and, therefore, it is well-suited to distinguishing between contemporaneous neuronal events.
On the other hand, functional magnetic resonance imaging is disadvantageous in comparison to electroencephalography and magnetic encephalography in several ways. First, it is laborious and slow to use functional magnetic resonance imaging to detect all of the neuronal events that make up a cascade. Second, functional magnetic resonance imaging is not well-suited for detecting the relative timing of neuronal events, which is necessary to ensure that the neuronal events in the cascade occur in the proper sequence. And third, functional magnetic resonance imaging does not directly detect a neuronal event, but only infers its occurrence by detecting some of its physiological effects. For example, a neuronal event at a region of the brain causes hemodynamic and metabolic effects at that region, and it is these hemodynamic and metabolic changes that the magnetic resonance imaging detects. For the purposes of this specification, the term xe2x80x9cphysiological effectxe2x80x9d is defined as a function of a living organism or any of its parts, and explicitly includes: hemodynamic effects or metabolic effects or both. Although neuronal events are well defined temporally, their associated hemodynamic and metabolic effects are not well-defined temporally, and, therefore, it is difficult to precisely detect when a neuronal event occurs by observing either its hemodynamic or metabolic effects.
FIG. 2 depicts a time line that shows the temporal relationship of a stimulus to one of the many neuronal events triggered (either directly or indirectly) by that stimulus and to the hemodynamic and metabolic effects caused by that neuronal event. As shown in FIG. 2, a stimulus occurs at time t=tS, which triggers a neuronal event at time t =tE, which in turn causes an apparent physiological effect some time later. Although the neuronal event is temporally well defined and might last only a few milliseconds, the physiological effect is not temporally well defined and typically occurs many seconds after the neuronal event. Therefore, it is difficult to detect when a neuronal event occurs with high temporal accuracy by observing its physiological effects.
Another well-known technique for studying brain activity is positron emission tomography (commonly known as xe2x80x9cPETxe2x80x9d) where a patient is injected with a O15 water injection and neuronal events are detected by observing changes in regional cerebral blood flow (commonly known as xe2x80x9crCBFxe2x80x9d). In this sense, positron emission tomography is similar to magnetic resonance imaging, but positron emission tomography does not enable diagnosticians to observe neuronal events in real time.
Therefore, the need exists for a technique that is capable of detecting the occurrence of neuronal events with high temporal accuracy and of distinguishing between contemporaneous neuronal events.
The present invention is a technique for studying brain activity that avoids some of the costs and disadvantages associated with techniques in the prior art. In particular, the illustrative embodiment of the present invention is a technique that is capable of detecting the occurrence of neuronal events in a brain with high temporal accuracy and of distinguishing between contemporaneous neuronal events. Furthermore, some embodiments of the present invention are advantageous in that they are noninvasive and enable the observation of neuronal events in real time. For these reasons, some embodiments of the present invention might be useful in medicine and neuroscientific research.
In accordance with the illustrative embodiment of the present invention, the brain activity of a subject is tested by observing whether one or more predicted neuronal events (that are part of a cascade of neuronal events triggered by a known stimulus under controlled conditions) do occur when and as expected. In other words, a known stimulus is administered to a subject under controlled conditions to trigger a predictable cascade of neuronal events. The subject is then observed using magnetic resonance imaging to determine when and if the predicted neuronal events do indeed occur. If they do not occur at all, or occur at times that are significantly different than expected, it might suggest a pathological condition in the subject. By performing a battery of such tests, the nature and location of the pathology might be determined.
To observe when and if a first neuronal event occurs as predicted, a cascade of neuronal events, which is expected to comprise the first neuronal event, is triggered by a first stimulus, in well-known fashion. Thereafter, the occurrence of the first neuronal event is inferred, in well-known fashion by using magnetic resonance imaging to detect the physiological effects of the first neuronal event. Although this alone does not determine when the first neuronal event occurred with high temporal accuracy, it does indicate whether a neuronal event is occurring or not at a particular region at approximately the predicted time. Furthermore, it provides a baseline of the physiological effects at that region at a given time with respect to the first stimulus.
Next, a second neuronal event is triggered by a second stimulus at a time interval before or after the first stimulus. Advantageously, the second stimulus and the time interval are chosen so that the second neuronal event and the first neuronal event occur at the same time and in the same region of the brain. If the first neuronal event and the second neuronal event do occur at the same time and at the same place, they will interfere, either constructively or destructively, which interference is manifested by different physiological effects than were caused by the first neuronal event alone (i.e., the baseline). In other words, the physiological effects at a region in response to one neuronal event are different than the physiological effects at the region in response to two interfering neuronal events. For example, one neuronal event may interfere with a second neuronal event by inhibiting the second neuronal event.
If the first neuronal event and the second neuronal event do not occur at the same time, there will be no interference, which is manifested by physiological effects that resemble the baseline. If the first neuronal event and the second neuronal event do not interfere, the time interval between the first stimulus and the second stimulus can be changed in an attempt to make them interfere. When the interference is detected, the time interval between the first stimulus and the second stimulus can be compared to a nominal range. If the time interval is outside of the nominal range, then it suggests that a pathological condition exists.
Because interference will only occur when the two short-lived and comparably well-defined neuronal events coincide in time, and will not occur if they are asynchronous, some embodiments of the present invention enable the detection of neuronal events with a high temporal resolution. And because magnetic resonance imaging equipment is used, it is easy to distinguish between, and to separately test, contemporaneous neuronal events.
The illustrative embodiment of the present invention comprises: stimulating a subject with a first stimulus to cause a first event in the subject; stimulating the subject with a second stimulus to cause a second event in the subject, wherein the second stimulus occurs at a temporal interval, xcex94tn, after the first stimulus, and wherein the first event and the second event jointly affect at least one characteristic of a first physiological effect at a first region of the subject as a function of the temporal interval, xcex94tn; and measuring the at least one characteristic of the first physiological effect at the first region of the subject.